Materials and methods for controlling infections

ABSTRACT

The subject invention provides materials methods for reducing infections in subjects. The materials methods utilize chlorhexidine, which has been found to be surprisingly non-toxic. The lack of toxicity facilitates the use of chlorhexidine in contexts that were not previously thought to be possible.

CROSS-REFERENCE TO A RELATED APPLICATION

This application is a continuation of co-pending application Ser. No.14/568,925, filed Dec. 12, 2014; which claims the priority benefit ofU.S. Provisional Application Ser. No. 61/915,281, filed Dec. 12, 2013,both of which are incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

The management and treatment of a wound, a surgical site, a surgicalincision, or otherwise infection-prone tissues in the body, has threeprimary objectives: (1) prevention of infection, (2) preservation and/orrestoration of function, and (3) preservation and/or restoration ofcosmetic appearance. The most important of these objectives is theprevention of infection. Success in the prevention of infection directlyaffects the healing process and the degree to which function andcosmetic appearance can be preserved and/or restored.

The number and virulence of bacteria present at a site are criticaldeterminants of whether the site becomes infected. Experimental evidencesuggests that a critical level of bacteria is approximately 10⁵organisms per gram of tissue. Below this level, a site or a tissuetypically heals; at levels greater than 10⁵ bacteria per gram of tissue,infections often develop. Dirty wounds, or wounds that have not beentreated within six hours, are likely to be contaminated with bacteria atlevels that are higher than the critical level. Reducing the number ofbacteria in and around the wound is critical for avoiding infection andexpediting wound healing.

Methicillin-resistant Staphylococcus aureus (MRSA) infection is causedby Staphylococcus aureus bacteria—often called “staph.” Decades ago,strains of staph emerged in hospitals that were resistant to thebroad-spectrum antibiotics commonly used to treat them. Theseantibiotics include methicillin and other more common antibiotics suchas oxacillin, penicillin, and amoxicillin. Dubbed methicillin-resistantStaphylococcus aureus (MRSA), it was one of the first germs to beresistant to all but the most powerful drugs.

Staph bacteria are generally harmless unless they enter the body througha cut or other wound. In older adults and people who are ill or haveweakened immune systems, ordinary staph infections can cause seriousillness. Staph infections, including MRSA, occur most frequently amongpersons in hospitals and healthcare facilities, such as nursing homesand dialysis centers, who have weakened immune systems; however, in the1990s, a type of MRSA began appearing in the wider community. Today,that form of staph, known as community-associated MRSA, or CA-MRSA, isresponsible for many serious skin and soft tissue infections and for aserious form of pneumonia. If not treated properly, MRSA infection canbe fatal.

MRSA infections in the community are usually manifested as skininfections, such as pimples and boils. These CA-MRSA infections canoccur in otherwise healthy people, and commonly occur among athletes whoshare equipment or personal items including towels and razors. In fact,from 2000 to present, there have been several reported outbreaks ofCA-MRSA affecting high school and professional athletic teams. Thisepidemic among athletes is aided by the fact that MRSA grows veryrapidly in warm, moist areas such as gyms and gym locker rooms. Commoncuts and abrasions such as those frequently occurring in football andbaseball now pose significant threats due to the possibility of an MRSAinfection.

MRSA infections are spreading rapidly in the United States andworldwide. According to the Center for Disease Control and Prevention(CDC), the proportion of infections that are antimicrobial resistant hasbeen growing. In, 1974, MRSA infections accounted for two percent of thetotal number of staph infections; in 1995 it was 22%; and in 2004 it wasnearly 63%. Additionally, recent research has suggested that 30-50% ofthe population carries MRSA colonies on their bodies all the time,helping to facilitate the spread of infection.

Vancomycin is one of the few antibiotics still effective againsthospital strains of MRSA infection, although the drug is no longereffective in every case. Several drugs continue to work against CA-MRSA,but CA-MRSA is a rapidly evolving bacterium, and it may be a matter oftime before it, too, becomes resistant to most antibiotics.

Chlorhexidine is a chemical antiseptic, and it combats both grampositive and gram negative microbes. It is bacteriostatic, hampering thegrowth of bacteria, and bacteriocidal, killing bacteria. It is oftenused as an active ingredient in mouthwash designed to kill dental plaqueand other oral bacteria. Chlorhexidine also has non-dental applications.For example, it is used for general skin cleansing, as a surgical scrub,and as a pre-operative skin preparation. Chlorhexidine is typically usedin the form of acetate, gluconate, or hydrochloride, either alone or incombination with other antiseptics such as cetrimide.

The use of chlorhexidine in wound irrigation applications has beenpreviously described. See, for example, U.S. Published Application No.2011-0288507A and U.S. Published Application No. 2011-0097372A, both ofwhich are incorporated herein, by reference, in their entireties.

BRIEF SUMMARY OF THE INVENTION

The current invention provides materials and methods for preventing ortreating an infection by administering a disinfectant compositioncomprising chlorhexidine, either directly or indirectly, to the site ofthe infection, or potential infection. In preferred embodiments, thedisinfectant composition is sterile.

Advantageously, it has been found that chlorhexidine-containingsolutions can be administered to a subject according to the currentinvention without causing hemolysis or other deleterious effects on theblood, blood cells, or vascular system. Furthermore, when administeredaccording to the procedures of the subject invention, thechlorhexidine-containing solutions of the subject invention do notresult in deleterious absorption of chlorhexidine, systemic toxicity, orfibrosis. Furthermore, the compositions of the subject invention can beapplied to tissue of the nervous system, including tissue of the centralnervous system (CNS), without causing deleterious effects.

Based on these findings it is now possible to utilizechlorhexidine-containing solutions in novel and advantageous ways, asdescribed herein, to effectively treat and/or prevent infections in awide range of tissues and locations in a subject.

Advantageously, the anti-microbial compositions of the subject inventionare useful against drug resistant microbes, including MRSA. Furthermore,microbes do not readily acquire resistance to the treatments of thesubject invention.

In a preferred embodiment, the active agent is chlorhexidine gluconate,preferably at a concentration of about 1.0% or less, more preferably atabout 0.1% or less, and even more preferably at about 0.05% or less, andfor some uses at 0.02% or less. Chlorhexidine dissolved in plain wateror in a salt-containing solution, saline for example, can be usedaccording to the current invention.

In certain embodiments, the administration of thechlorhexidine-containing solution is followed by a rinse with, forexample, saline. In other embodiments, no such rinse is applied. Incertain embodiments, such as in the case of surgeries and/or irrigatinga body cavity, the administration of chlorhexidine can be followed bysuction. The suction may be applied, for example, 1 to 5 minutes afterthe chlorhexidine is administered.

The aqueous solution, or other material, containing chlorhexidine mayhave other components including, for example, pH modifiers, buffers,local anesthetic agents, agents that promote wound healing (such asagents that help degrade biofilm), agents that stop bleeding and/orpromote clot formation, and other therapeutic and non-therapeuticcomponents. In one embodiment, the composition “consists essentially” ofan aqueous solution of CHG, which means that the solution contains noother active agent that materially changes the ability of the solutionto control microbial growth.

The disinfectant composition of the current invention can be used in avariety of applications directed at preventing and/or treatinginfections. Treatment can be applied at, for example, a surgical site, asurgical incision on the skin, the blood, the urogenital tract, animplant, a joint, the respiratory tract, an intraperitoneal site, anocular site, the colon, the sinuses, an intra-articular site, amediastinal site, a healing tissue site, intracranial, or acerebrospinal site, or other nervous system tissue.

The current invention also provides kits and trays comprising thedisinfectant composition and apparatuses or devices for administrationof the disinfectant composition to the subject. In preferred embodimentsthe composition, the kits and the trays are sterile.

DETAILED DESCRIPTION OF THE INVENTION

The current invention provides materials and methods for preventingand/or reducing the development of an infection or treating an existinginfection at a site in a subject. The subject may be, for example, ahuman or other animal.

Chlorhexidine-containing solutions can be administered to a subjectaccording to the current invention without causing hemolysis or otherdeleterious effects on the blood, blood cells, or vascular system.Furthermore, when administered according to the procedures of thesubject invention, the chlorhexidine-containing solutions of the subjectinvention do not result in deleterious absorption of chlorhexidine,systemic toxicity, or fibrosis. Additionally, the compositions of thesubject invention can be applied to tissue of the nervous system,including tissue of the central nervous system (CNS), without causingdeleterious effects.

Based on these findings it is now possible to utilizechlorhexidine-containing solutions in novel and advantageous ways, asdescribed herein, to effectively treat and/or prevent infections in awide range of tissues and locations in or on a subject.

Advantageously, the anti-microbial compositions of the subject inventionare useful against drug resistant microbes, including MRSA. Furthermore,microbes do not acquire resistance to the treatments of the subjectinvention.

In one embodiment, the method of the subject invention comprises thesteps of:

(a) providing a sterile disinfectant composition comprising an activeagent comprising chlorhexidine at a concentration of about 1% or less,and

(b) administering the sterile disinfectant composition, directly orindirectly, to the site in the subject.

The site to which the chlorhexidine is applied can be any site that isat a risk of developing an infection or has an existing infection.Non-limiting examples of sites that are appropriate for the practice ofthe method of the current invention include surgical sites, surgicalincisions on the skin, the blood, the urogenital tract, implants, therespiratory tract, intraperitoneal sites, ocular sites, the colon, thesinuses, an intra-articular site, a mediastinal site, intracranial, acerebrospinal site or other nervous system tissue.

Advantageously, the disinfectant composition of the subject invention iseffective in combating infection, even when organic materials (includingblood, tissue, and/or dirt and debris) are present.

The sterile disinfectant composition of the current invention containsan active agent that preferably comprises chlorhexidine at aconcentration of less than about 1%, less than about 0.1%, less thanabout 0.05%, less than about 0.025%, or less than about 0.02%. Thechlorhexidine can be, for example, chlorhexidine gluconate (CHG),chlorhexidine acetate, chlorhexidine hydrochloride, or a combinationthereof. The chlorhexidine may also be modified with, for example, aphosphate group to enhance efficacy, further reducing the likelihood ofthe development of resistant microbes. The disinfectant composition canfurther contain one or more additional active agents. In certainembodiments, the composition contains no alcohol, or less than 1%, 5%,10%, 25%, or 50% alcohol.

In specific embodiments, the compositions of the subject invention canbe used to prevent or reduce the formation of biofilm in, for example,the context of surgical implants, stents, catheters, and otherindwelling medical devices. The chlorhexidine containing solutions canbe used to reduce the formation of biofilm in other contexts as well,including, for example, biofilm associated with sinus infections andpink eye.

In certain embodiments, chlorhexidine can be incorporated into anindwelling medical device itself and/or a coating that can be applied tosuch a device. If desired the chlorhexidine can be released over timethrough the use of, for example, an appropriate hydrogel or otherpolymer. In specific embodiments, the chlorhexidine can be releasedpreferentially in the presence of an infection. This can be accomplishedby, for example, incorporating the chlorhexidine into a material thatreleases the chlorhexidine when a pH change associated with the presenceof the bacteria occurs.

Further embodiments of the subject invention include nasal sprays orother forms of nasal irrigation solutions to facilitate nasal irrigationto treat infections, including those caused by antibiotic resistantmicrobes such as MRSA. In one embodiment, the invention provides amethod for treating a nasal infection by administering to a subject thathas been diagnosed with a nasal infection, a solution containing ananti-infective amount of chlorhexidine. In one embodiment thechlorhexidine is CHG. In another specific embodiment, the infection is aMRSA infection.

In a further embodiment, the compositions of the subject invention canbe used to prevent or reduce eye infections.

Other uses include administering chlorhexidine in the context of breastimplants or collagen implants to reduce the likelihood of infection andthe need for follow up surgery.

Chlorhexidine solutions of the subject invention can also be usedaccording to the subject invention to disinfect acupuncture needles,earrings and other piercing objects that can then be inserted into thebody.

Even further, a urogenital tract irrigation system can be used toadminister the sterile disinfection composition to the urogenital tractof the subject.

The disinfectant composition of the subject invention can also beadministered to the respiratory system of the subject.

Additionally, a cerebrospinal irrigation system can be used toadminister the sterile disinfectant composition to a site in the nervoussystem of a subject.

The use of CHG in wound irrigation applications has been previouslydescribed. See, for example, U.S. Published Application No.2011-0288507A and U.S. Published Application No. 2011-0097372A, both ofwhich are incorporated herein, by reference, in their entireties. Thosepatent applications describe various uses of CHG-containing solutions.In certain embodiments, the materials and compositions of the currentinvention specifically exclude those uses that were described in U.S.Published Patent Application Nos. 2011-0288507A and 2011-0097372A.

The terms “about,” “approximately,” “approximate,” and “around” are usedin this patent application to describe some quantitative aspects of theinvention, for example, the concentration of the active agent. It shouldbe understood that absolute accuracy is not required with respect tothose aspects for the invention to operate. When these terms are used todescribe a quantitative aspect of the invention the relevant aspect maybe varied by up to ±10%. Thus, the terms “about,” “approximately,”“approximate,” and “around” allow for variation of the various disclosedquantitative aspects of the invention by ±1%, +2%, +3%, +4%, +5%, ±6%,+7%, +8%, ±9%, or up to ±10%. For example, a sterile disinfectantcomposition comprising about 1% active agent can contain 0.9% to 1.1%active agent.

Advantageously, the disinfectant composition of the subject invention iseffective in combating infection, even when organic materials (includingblood, tissue, and/or dirt and debris) are present.

Formulations

In one embodiment of the subject invention, a low concentration solutionof chlorhexidine can be used to effectively prevent or treat infections.Advantageously, it has been found that the chlorhexidine-containingsolutions can be administered to a subject according to the currentinvention without causing hemolysis or other deleterious effects on theblood, blood cells, or vascular system. Furthermore, when administeredaccording to the procedures of the subject invention, thechlorhexidine-containing solutions of the subject invention do notresult in deleterious absorption of chlorhexidine, system toxicity, orfibrosis. Furthermore, the compositions of the subject invention can beapplied to tissue of the nervous system, including tissue of the centralnervous system (CNS), without causing deleterious effects.

Based on these findings it is now possible to utilizechlorhexidine-containing solutions in novel and advantageous ways, asdescribed herein, to effectively treat and/or prevent infections in awide range of tissues and locations in a subject.

In specific embodiments, the chlorhexidine concentration is less thanabout 2%, less than about 1%, or less than about 0.1%. In a furtherembodiment, the chlorhexidine concentration is less than about 0.05%. Ineven further embodiments, the chlorhexidine concentration is between0.02% and 0.05%. Specifically exemplified herein is the use of CHG.

In a specific embodiment, the CHG used according to the subjectinvention has the following chemical structure:

CHG Systematic 1-[amino-[6-[amino-[amino-(4-chlorophenyl)amino- (IUPAC)Name methylidene]amino-methylidene]aminohexylimino]methyl]imino-N-(4-chlorophenyl)-methanediamine Chemical Data FormulaC₂₂H₃₀Cl₂N₁₀ Mol. weight 505.446 g/mol

The pH of the disinfectant composition is preferably neutral or slightlyacidic. Preferably the pH is 5.0 to 7.5. More preferably the pH is 5.5to 7.0.

In a preferred embodiment, the administration of the disinfectantcomposition of the current invention to an infection site results in areduction in the number of bacteria or other microbes at the site whencompared to either an untreated site or a site administered with salineor water that does not contain chlorhexidine. Advantageously,administration of the disinfectant composition according to the subjectinvention can result in effective control of an infection withoutcausing tissue damage.

Examples of additional active agents that can be administered to asubject in accordance with the subject invention include, but are notlimited to, anti-bacterial agents, anti-viral agents, fungicidal agents,chemotherapeutic agents, topical antiseptics, anesthetic agents,oxygenated fluids and/or agents, antibiotics, diagnostic agents,homeopathic agents, agents that stop bleeding, and over-the-countermedications/agents. In one embodiment, the additional agent can be ananti-microbial peptide (AMP). AMPs are well known in the art.

In certain embodiments, the additional agent is a diagnostic agent. Thediagnostic agent may be, for example, an antibody, protein, orpolynucleotide that binds to a target biomolecule. Any such binding maythen be visualized utilizing technologies known to those skilled in theart.

For the purpose of this invention, a plain aqueous solution of theactive agent comprises the active agent and/or a second agent in asolution of water that is essentially devoid of solutes that provideosmolarity to the solution, for example, a salt or a sugar. For thepurpose of this invention, an isotonic solution refers to a solutionhaving the same osmotic pressure as blood. Typically, isotonic solutionscontain about 0.85% of NaCl in water. Accordingly, an isotonic solutioncontaining the active agent according to the current invention refers toa solution of the active agent and/or a second agent in about 0.85% NaClin water.

Spectrum of Activity

Chlorhexidine is active against aerobic and anaerobic gram-positive andgram-negative bacteria. Chlorhexidine also has activity againstChlamydia trachomatis, certain fungi, and certain viruses.

Chlorhexidine is highly active against a variety of gram-positiveaerobic bacteria, including Streptococcus mutants, S. pyogenes (group Aβ-hemolytic streptococci), S. salivarius, and S. sanguis. Chlorhexidineis active against Staphylococcus aureus, S. epidermidis, S.haemolyticus, S. hominis, and S. simulans. Chlorhexidine is activeagainst both oxacillin-resistant (ORSA) and oxacillin-susceptiblestaphylococci (also known as methicillin-resistant [MRSA] ormethicillin-susceptible staphylococci). Chlorhexidine is active againstEnterococcus, including E. faecalis and E. faecium, and is activeagainst both vancomycin-susceptible and vancomycin-resistant strains.

Chlorhexidine is also active against some anaerobic bacteria.Chlorhexidine is active against some strains of Bacteroides,Propionibacterium, Clostridium difficile, and Selenomonas, but is lessactive against Veillonella.

Chlorhexidine has activity against Candida albicans, C. dubliniensis, C.glabrata (formerly Torulopsis glabrata), C. guillermondii, C. kefyr(formerly C. pseudotropicalis), C. krusei, C. lusitaniae, and C.tropicalis (formerly C. parapsilosis). Chlorhexidine also has activityagainst dermatophytes, including Epidermophyton floccosum, Microsporumgypseum, M. canis, and Trichophyton mentagrophytes.

Chlorhexidine also has antiviral activity against viruses that have alipid component in their outer coat or have an outer envelope such ascytomegalovirus (CMV), human immunodeficiency virus (HIV), herpessimplex virus types 1 (HSV-1) and 2 (HSV-2), influenza virus,parainfluenza virus, and variola virus (smallpox virus).

In addition to killing bacteria, the sterile disinfectant composition ofthe subject invention can also “depathogenize” certain bacteriaincluding, for example, Escherichia coli and Klebsiella aerogenes,making these bacteria less potent to cause infection.

In a preferred embodiment, the administration of the disinfectantcomposition of the current invention to an infection site results in areduction in the number of bacteria or other microbes at the site whencompared to either an untreated site or a site administered with salineor water that does not contain chlorhexidine. Advantageously, andunexpectedly administration of the disinfectant composition according tothe subject invention can result in effective control of an infectionwithout causing tissue damage.

Modes of Administration

The methods of the subject invention can be used in conjunction with thedelivery of a chlorhexidine-containing solution by many routes. Ofparticular interest are: cutaneous, intra-abdominal, intracranial,intralesional, intrathoracic (during surgery), nasal, in the ear canal,as an oral bowel prep, gastric lavage, as an eye wash, periodontal,rectal, soft tissue, subcutaneous, and vaginal routes.

Chlorhexidine solutions of the subject invention can be administeredusing any of a wide range of currently-available delivery devices,systems, and methods. These include delivery via catheter to treat arange of pathologies, or potential pathologies, including, but notlimited to, urinary tract infections, bloodstream infections,intracranial infections, and joint infections. In certain embodimentsthe chlorhexidine solution can be administered via a syringe to treatand/or prevent spinal cord infections including, but not limited to, forexample, meningitis.

The chlorhexidine solutions of the current invention can also beformulated as a spray or mist to treat appropriate sites such as chronicwounds and burns, or for nasal administration.

In a further embodiment, the subject invention provides a full-body orpartial-body shower to disinfect a subject who has been, or is suspectedof having been, exposed to a pathological agent such as, for example, inthe context of a biological weapon.

The chlorhexidine solution of the subject invention can also beformulated for inhalation by, for example, people suffering frompneumonia or other respiratory tract infections. In a specificembodiment, the chlorhexidine solution is formulated for inhalation bycystic fibrosis (CF) patients who have developed a lung infection or whoare at risk for developing such an infection. In a specific embodiment,the subject has been diagnosed with (CF).

In a further embodiment, chlorhexidine can be incorporated into amaterial that can be used to disinfect skin and other bodily surfacesincluding, for example, the ear canal. The material may be, for example,a wipe, cloth, or swab. Preferably, the wipe, cloth, swab, or otherchlorhexidine-containing material can be formulated for use even onsensitive skin such as the skin of babies or the elderly. Such wipes,cloths, swabs, and other materials can then be used in place of showersor baths for individuals who cannot readily shower or bathe. In specificembodiments, the material into which chlorhexidine has been incorporateddoes not include alcohol, or include less than 1% or less than 5%alcohol.

Examples of washcloths for body cleansing include U.S. Pat. Nos.5,725,311; 5,906,278; 5,956,794; 6,029,809, and 8,221,365, all of whichare incorporated herein in their entireties. In preferred embodiments,the material is impregnated with a solution comprising 1% or less ofchlorhexidine and, preferably 0.05% or less. Other ingredients can beadded including, for example, moisturizers.

In one embodiment of the current invention the sterile disinfectantcomposition can be administered to an internal surgical site (or othersite of infection or potential infection) via depositing a porousmaterial containing the active agent that releases the active agent overa period of time to the site. The presence of the active agent in andaround the site can prevent and/or treat an infection. The porousmaterial containing the active agent can be administered to a surgicalsite when the surgery is performed. In certain embodiments of theinvention, the porous material is a disc, a sphere, or a shape designedto fit at the site.

The porous material containing the active agent can release the activeagent over a period of about 1 hour to about 6 months, about 2 months toabout 5 months, about 3 months to about 4 months, about 1 week to about4 weeks, about 2 weeks to about 3 weeks, or any other permutation ofthese time periods.

Non-limiting examples of materials that can be used to produce theporous implants include silicate feldspar matrix, hydroxyapatite, poroustitanium, or sponge. Additional examples of materials appropriate toproduce sustained release implants are well known to a person ofordinary skill in the art and such materials are within the purview ofthe current invention. For example, Hydrogels or other such coatingsthat incorporate therein chlorhexidine can also be used.

In preferred embodiments of the invention, the disinfectant compositionis administered to a site of healing tissue. For the purpose of thisinvention, a healing tissue site is an area of the tissue that sufferedan injury or a disease and is recovering after the treatment for theinjury or the disease. A healing tissue site can be at the surface ofthe skin or internal.

In certain embodiments of the current invention, the disinfectantcomposition is administered to a healing tissue site via a patch,bandage, or dressing containing the chlorhexidine; a thick viscoussolution containing the chlorhexidine; or a suture containingchlorhexidine.

Advantageously, chlorhexidine binds to healing tissues, for example, tosub-cutaneous layers of skin, to provide antimicrobial and/or healingeffect. Accordingly, the sterile disinfectant composition of the currentinvention provides an active agent that can bind to a healing tissue toenhance healing tissue recovery, prevent infection, and/or treat anexisting infection.

In additional embodiments of the invention, the sterile disinfectantcomposition can be administered to a site as a tablet taken orally,microcapsule delivery spheres, nanoparticles, targeted nanoparticles(for example, receptor mediated targeted nanoparticles), a timecontrolled delivery system, a frozen block of the sterile disinfectantcomposition, a plain aqueous solution of the active agent, an isotonicsolution of the active agent, or an implantable time release deliverysystem. In certain embodiments, the disinfectant composition is left atthe site after administration thereto.

In a further embodiment of the invention, after administration of thedisinfectant composition of the current invention to a site or a tissue,the site or the tissue is rinsed with, for example, a sterile solutionfree of the active agent. Examples of solutions free of the active agentinclude, but are not limited to, plain water, saline, and isotonicsolutions free of the active agent. The rinsing can be performed byadministering the solution free of the active agent to the site andremoving the resultant solution from the site or the tissue by, forexample, suction. In certain embodiments, the rinsing is performedwithin about 1 minute to about 10 minutes, about 2 minutes to about 5minutes, or about 3 minutes from the time of administering the steriledisinfectant composition to the site in the subject. In otherembodiments, suction is performed, with or without rinsing.

Under optimal circumstances, the methods of the subject invention areutilized by trained medical technicians; however, because of thesimplicity and convenience of the subject invention, they can be used togreatly enhance the effectiveness of the administration of thedisinfectant composition regardless of the training level of theoperator performing the irrigation.

The subject can be a mammal. Non-limiting examples of mammals that canbe treated according to the methods of the current invention includehumans, non-human primates, dogs, cats, equines, bovines, and pigs.

Following are examples that illustrate procedures for practicing theinvention. These examples should not be construed as limiting.

Example 1—Surgical Applications

In one embodiment of the current invention, the sterile disinfectantcomposition is administered to a surgical site to prevent or treat aninfection at the surgical site. The surgical sites may include, forexample, joint replacements, abdominal surgery, brain surgery, andoral/periodontal surgery sites.

An infection developed at the surgical site is referred to herein as“surgical site infection” or “SSI.” A surgical site is at a risk ofdeveloping an SSI from, for example, improperly handled surgicalinstruments or airborne infectious agents from the operating room. SSIcan be treated by administering antibiotics to the patients; however,often a second surgery is required to treat the SSI. The additionalsurgery to treat SSI is undesirable for several reasons, for example,repeated trauma of surgery to the patient, risk of repeated infection,improper healing of the surgical site, and additional costs.

The current invention provides an easy and inexpensive alternative tothe second surgery for treating an SSI. The method of the currentinvention as it applies to treating the SSI comprises administering tothe surgical site the sterile disinfectant composition comprising anactive agent that comprises chlorhexidine at a concentration of about 1%or less, about 0.05% or less, or about 0.02% or less.

The sterile disinfectant composition can be administered to the surgicalsite as a plain aqueous solution, an isotonic solution, or othersalt-containing solution of the active agent. In one embodiment, after aperiod of time sufficient for the active agent to kill and/or inhibitthe growth of an infectious agent the surgical site can be rinsed with asterile solution free of the active agent. Alternatively, oradditionally, suction can be applied to the site. The period of timesufficient for the active agent to kill and/or inhibit the growth of theinfectious agent can be about 1 minute to about 10 minutes, about 2minutes to about 8 minutes, about 3 minutes to about 7 minutes, about 4minutes to about 6 minutes, or about 5 minutes.

In one embodiment, a chlorhexidine solution is administered inconjunction with robotic or other minimally invasive surgeries (MIS) inorder to reduce the risk of infection. In this context, tubing thatdelivers the chlorhexidine solution can be included with other tubes(e.g. tubes with optical components, tubes for delivery or removed orother fluids or tissue, and tubes for manipulating devices) that deliveror remove material from the surgery site, or which otherwise assist inthe procedure.

Thus, in one embodiment, the subject invention provides an MIS systemhaving, as one component, a tube through which achlorhexidine-containing solution is discharged at a distal end of thetube. The proximal end of the tube may be configured to receive thechlorhexidine-containing solution from a reservoir that may be, forexample, a bag, bottle, or other suitable container. Preferably thesystem is sterile. The system can have further tubes and other elementsuseful for conducting a MIS procedure.

The MIS system can be adapted for surgeries including, for example,coronary, vascular, prostrate, laparoscopic, spinal, and neurological.

Example 2—Intravascular Administration

In another embodiment of the invention, the disinfectant composition canbe administered to the blood of a subject via intravascular injection.

Preferably, the injection is intravenous. The disinfectant compositioncan be a plain aqueous solution, an isotonic solution, or othersalt-containing solution that contains chlorhexidine.

In certain embodiments of the invention, an isotonic solution containingthe chlorhexidine is freshly prepared before administration to thesubject. For example, the isotonic solution containing the active agentcan be prepared, less than 1 minute, less than 2 minutes, about 1 minuteto about 30 minutes, about 5 minutes to about 20 minutes, about 10minutes to about 15 minutes before the intravascular injection, or anyother permutation of these time periods.

In certain embodiments an isotonic solution containing chlorhexidine isprepared by mixing a salt solution and chlorhexidine in an appropriatequantity of water. In certain embodiments, a volume of a plain aqueoussolution of the chlorhexidine containing twice the concentration ofchlorhexidine compared to the desired concentration of chlorhexidine inthe final working solution is mixed with equal volume of a solutionhaving 2× isotonicity of the isotonic solution to prepare the isotonicsolution of chlorhexidine appropriate for administration into asubject's blood.

Example 3—Urogenital Tract Applications

In a further embodiment of the invention, the sterile disinfectantcomposition can be administered to the urogenital tract of a subject viaa urogenital tract irrigation system.

A urogenital tract irrigation system refers to an apparatus useful forflushing one or more organs of the urogenital tract. Non-limitingexamples of urogenital tract irrigation system include bladderirrigation systems and urethral irrigation systems.

The sterile disinfectant solution used in urogenital tract irrigationsystem can be for example, a plain aqueous solution of the active agentor an isotonic solution of the active agent.

Example 4—Intra-Articular Applications and Indwelling Devices

In an even further embodiment of the current invention, the steriledisinfectant composition is administered to an intra-articular site viaan intra-articular injection. The intra-articular sites that can beinjected according to the methods of the current invention include, butare not limited to, elbow, shoulder, wrist, hip joints, knees, ankles,and intervertebral sites.

In an even further embodiment of the current invention, the disinfectantcomposition can be administered to the site of an implant or otherindwelling device by incorporating the sterile disinfectant compositioninto or onto the implant or other devices.

For the purpose of this invention, an implant refers to a medical devicedesigned to remain in the body for an extended period of time. Theextended period of time may be, for example, more than 5 minutes, morethan 1 hour, more than 12 hours, more than a day, more than a week, morethan a month, and/or more than a year.

The implant may be designed to, for example, replace a missingbiological structure, support a damaged biological structure, or enhancethe function of an existing biological structure. Implants are man-madedevices, in contrast to a transplant, which is a transplanted biomedicaltissue.

The surface of implants that contact the tissue of the subject can bemade of a biomedical material such as titanium, silicone, hydrogel (orother polymer) or apatite. In some cases implants contain electronics,e.g., artificial pacemakers and cochlear implants.

The active agent can be incorporated into the implant, which thenreleases the active agent over a period of time. The materials and timedurations discussed above in connection with porous materials used totreat infections are also applicable to this embodiment of the currentinvention.

Example 5—Respiratory System Applications

The chlorhexidine solution of the subject invention can also beformulated for inhalation by, for example, people suffering frompneumonia or other respiratory tract infections. In a specificembodiment, the chlorhexidine solution is formulated for inhalation bycystic fibrosis (CF) patients who have developed a lung infection or whoare at risk for developing such an infection. In a specific embodiment,the subject has been diagnosed with (CF).

The disinfectant composition can be administered to the respiratorytract of a subject via inhalation of, for example, vapors, particles,and/or aerosols containing the active agent. Non-limiting examples ofdevices appropriate for producing vapors, particles and/or aerosols forinhalation of the active agent include inhalers and puffers. Additionalexamples of devices that can be used to produce inhalable vapors,particles and/or aerosols are well known to a person of ordinary skillin the art and such embodiments are within the purview of the currentinvention.

Example 6—Body Cavity Applications

In one embodiment of the invention, the disinfectant composition isadministered to a body cavity, such as an intraperitoneal site, viainjection, infusion, or irrigation of the sterile disinfectantcomposition.

The disinfectant composition injected into the intraperitoneal site canbe, for example, a plain aqueous solution of chlorhexidine, an isotonicsolution, of a gel containing chlorhexidine, an emulsion, or asuspension.

Example 7—Ocular Applications

In certain other embodiments of the current invention, the steriledisinfectant composition is administered to an ocular site as anophthalmic composition containing chlorhexidine. The ophthalmiccomposition can be, for example, a solution, suspension, or an ointmentcontaining the active agent.

In a specific embodiment, a chlorhexidine solution is applied to the eyein conjunction with an eye surgery procedure. The eye surgery proceduremay be, for example, cataract surgery, retina surgery, lense replacementsurgery, or surgery to correct traumatic damage including, but notlimited to, corneal abrasion. The chlorhexidine solution may be appliedbefore, during, or after the surgery. The chlorhexidine solution of thecurrent invention can also be used to treat pink eye.

The concentration of the chlorhexidine may be less than 1%, preferablyless than 0.16%, less than 0.05%, less than 0.02%, or even less than0.01%. The administration of the chlorhexidine solution may be followedby a rinse with, for example, saline, but does not have to be followedby a rinse.

In one embodiment, the subject invention provides a container with asterile chlorhexidine solution with an eye dropper contained therein, orassociated therewith. The container may itself be sterile for use in asurgical setting.

Example 8—Use for Chronic Wounds and Burns

In additional embodiments, the chlorhexidine compositions of the currentinvention can be used for the treatment of acute and/or chronic woundsand burns. In this context, chlorhexidine can be incorporated intodressings or formulated into pastes or mists that do not causediscomfort upon application to the chronic wound or burn site.

Example 9—Sub-Dermal Applications

In a further embodiment, the chlorhexidine-containing compositions canbe injected to treat sub-dermal infections such as might occur at thesite of a breast implant. Advantageously, such infections can be treatedaccording to the subject invention without the need for a furtherinvasive procedure.

In accordance with the subject invention it has been found thatchlorhexidine advantageously binds to subcutaneous tissue. Repeatedapplication increases the chlorhexidine bound to tissue thereby creatinga cumulative effect that facilitates the establishment of a barrierlayer of protection against infection. In specific embodiments,chlorhexidine is applied repeatedly, or continuously, to achieveenhanced protection against infection via the establishment of anantimicrobial layer.

Example 10—Piercings and Acupuncture

The compositions according to the subject invention can also beincorporated into, or applied to, ear rings and other body piercingitems, and acupuncture needles to reduce the incidence of infectionassociated with body piercings and/or acupuncture.

Example 11—Oral Administration

In a further embodiment, the chlorhexidine-containing compositions ofthe subject invention can be formulated for oral delivery for treatmentof sore throats as well as digestive tract maladies. In this context,the compositions of the subject invention can be used to treat the fluor other viruses as well as food poisoning and bacteria associated withulcers and digestive tract inflammation.

Example 12—Treatment of Nasal Infections

In further embodiments of the current invention, the steriledisinfectant composition is administered to the sinuses via a nasalirrigation system, a nasal swab, a nasal lavage, a nasal douche, or aneti pot. A nasal irrigation system is designed to rinse sinuses andflush out clogged nasal passages using a solution, for example, a saltsolution, a plain aqueous solution, or an isotonic solution of theactive agent. Additional embodiments of nasal irrigation systems arewell known to a person of ordinary skill in the art and such embodimentsare within the purview of the current invention.

Example 13—Nervous System Applications

In certain embodiments of the current invention, the steriledisinfectant composition is administered to a cerebrospinal site viacerebrospinal injection or cerebrospinal irrigation.

Example 14—Sutures

Additionally, sutures containing chlorhexidine may be used to stitch asurgical incision or a wound of a subject. The sutures can then releasethe chlorhexidine to the site of administration over a period of time.Chlorhexidine can also be added, according to the subject invention, tosurgical glues and liquid bandages.

Example 15—Kits and Trays

A further embodiment of the current invention provides kits comprisingthe sterile disinfectant composition and apparatuses or devices foradministration of the sterile disinfectant composition to the site ofthe subject.

The apparatuses and the devices for the administration of the steriledisinfectant composition to the site of the subject include, but are notlimited to, a bottle for administering the plain aqueous solution of theactive agent or the isotonic solution of the active agent to the site, atransdermal patch, a porous material, a sponge, sutures, a urogenitaltract irrigation system, an implant, a vapor inhalation device, a nasalirrigation system, a nasal lavage, a nasal douche, a neti pot, aninjection system, or a cerebrospinal irrigation system. This can also beachieved via the port on minimally invasive surgery trocars and othersuch devices

For the purpose of the current invention, an injection system cancomprise a syringe and a needle and/or a catheter. The size of theneedle and the syringe depend on the site to which the steriledisinfectant composition is administered. A person of ordinary skill inthe art can determine the appropriate size of the syringe and the needlein a particular situation.

Non-limiting examples of the kits and trays according to the currentinvention include, a plain aqueous solution of the active agent, anisotonic solution of the active agent, a plain aqueous solution of theactive agent at a 2× concentration of the active agent compared to thefinal working solution and a solution free of active agent having 2×isotonicity, the active agent in a solid form and sterile water orsterile isotonic solution, a transdermal patch containing the activeagent, a porous material containing the active agent, a spongecontaining the active agent, a thick viscous solution containing theactive agent, a mist spray containing the active agent, suturescontaining the active agent, a urogenital tract irrigation system and asterile disinfectant composition, an implant containing the activeagent, a vapor inhalation device and a sterile disinfectant composition,an aerosol inhalation device and a sterile disinfectant composition, anophthalmic emulsion containing the active agent, an ophthalmic solutioncontaining the active agent, an ophthalmic suspension containing theactive agent, an ophthalmic ointment containing the active agent, anasal irrigation system and a sterile disinfectant composition, a nasallavage and a sterile disinfectant composition, a nasal douche and asterile disinfectant composition, a neti pot and a sterile disinfectantcomposition, an injection and a sterile disinfectant composition, or acerebrospinal irrigation system and a sterile disinfectant composition.

The kits and trays (including custom packs) can be used to practice themethods of the current invention. For example, a user can use a kitcomprising a plain aqueous solution of the active agent or the isotonicsolution of the active agent by administering the solution of the activeagent to the site of the subject. Similarly, a user can mix equalamounts of the plain aqueous solution of the active agent at a 2×concentration and the solution free of active agent having 2×isotonicity to prepare a working isotonic solution of the active agent.A user can also dissolve the active agent in the solid form in sterilewater or sterile isotonic solution to prepare a working isotonicsolution of the active agent.

It should be understood that the examples and embodiments describedherein are for illustrative purposes only and that various modificationsor changes in light thereof will be suggested to persons skilled in theart and are to be included within the spirit and purview of thisapplication and the scope of the appended claims.

We claim:
 1. A method for treating a biofilm infection at a site in asubject, wherein said method comprises administering, to the biofilm, anaqueous solution having an active ingredient that consists ofchlorhexidine at a concentration of 0.05% or less, wherein the site isan indwelling medical device.
 2. The method of claim 1, wherein thechlorhexidine is chlorhexidine gluconate.
 3. The method, according toclaim 1, wherein the indwelling medical device is an implant, stent, orcatheter.
 4. The method of claim 1, wherein biofilm is determined toexist at the site prior to the administration of the chlorhexidine. 5.The method, according to claim 1, wherein the subject is a human.